Interview with an FDA Process Expert - PART 2
ADDITIONAL QUESTIONS
(Some of these I took from your questions that you guys asked in our thread and a few additional ones from me). Thanks to each respective author for your questions, needless to say the interview time flew by, could've chatted to him for another hour easily, my lunch hour at work was over before I knew it!).
QUESTION 4 - In the scheme of things, how does a 30,000 page submission compare? What would be the average? What is the largest you have heard of?
Average is "many thousands of pages".
He went on to state that its typical with these sorts of submissions that defensive writing is deployed, the sponsor needs to show and document any assumptions, this adds to the amount of evidence and text. It's always beneficial to include more info to really protect oneself to pre-empt questions that could be asked later on.
Mr X added that 30 K pages is big, but in the case of some of the stem cell and newer technologies, submissions have been larger again.
QUESTION 5 - We are applying for Fast Track designation, if we have pre determined trials that are to span over some 1.5 years, a fast track designation can't really help in this area, my view is that it would really help after the read out up until and including registration? Is this true? Can it help in any other way?
Does the sponsor apply for this, what about Breakthrough/Priority once data comes back?Fast Track designation augments the ability to speed up the trial process through the observation that a significant unmet need or sense of urgency is required.
We had a really insightful conversation here. The beauty of Fast Track is that "it can limit what else you may have to do", it can tip the balance in your favour apart from a modest speeding up of processes, mainly after the clinical trial. (Eg between read out and Registration for example).
Mr X specifically mentioned the rampant misuse and destructiveness of opioids as a poor std of care in our case and seemed to think this will only add to our submission and ability for such a designation to be considered.
(Mozz notes: The whole Opioid situation adds a degree of urgency with some 112 Americans dying every day, quite apart from the increase comorbidities that result from people not being able to exercise and be active due to pain from OA)). However Mr X did infer that the FDA will be more inclined to perhaps speed things up if the data that comes back starts looking really efficacious and safe. It did sound like its very much a sponsor invoked application in terms of making a case once good data flows back.
QUESTION 6 - When is fast track determined?
I asked this question as I wanted to know at what point this is often deemed.
Mr X said usually it can happen at or after IND, typically the FDA would give a sponsor the indication as to whether they are eligible for a Fast Track designation at this point but he said not to get too excited as what can happen is that the FDA may hint that we are eligible for such a designation and will map out a set pathway for this to occur at a later point. ie if the sponsor does this, this and this and it is shown that this occurs, then the sponsor may be eligible for such a designation as an example Mr X stated that you may get some sort of designation like fast Track but the official letter stating the Fast Track has been awarded may not come until after a successful dosing study is completed or a further and subsequent milestone/condition is met.
What gives me more enthusiasm is the fact that Mr X suggested there was always a possibility that if the data looks good, if the sponsor is meeting all the requirements AND the data that comes back correlates to a higher degree of safety AND this falls within the backdrop of a poor current standard of care, the chances of interim analysis and the Sponsor having the ability to suggest to the FDA a review of the data which can lead to a shorter path to registration. Caveats and conditions can always be imposed if this occurs, ie the FDA could say YES but subject to close ongoing current patient monitoring as an example. It was interesting that this is mainly Sponsor driven.
MOZZ view: I give you two points here
A) It is up to the sponsor (that's us) to instigate a chat with the FDA if the sponsor believes there is a definite case for an interim data read if the data is looking compelling and there are no safety concerns.
B) Yes it may seem like its a good 2 to 3 years before we could get approved, but this is not the ONLY PATH FORWARD. You get compelling data (Don't forget the additional 008 data here) and things could work out QUICKER. I'm not sure of the chances, I'm not personally banking on it myself...but deep in the back of my mind, I know it is a possibility. (The shorters are not aware of this ...)
Mr X also suggested that the FDA should not be thought of as a "gatekeeper' or a "bouncer at a nightclub", their ultimate goal is to get a good drug out to the population. Mr X also commented the FDA will never tell the sponsor what to do.
From here he then went on to ask about what experience our top management had with the FDA. That was an easy one as I rattled off the experience our staff had in terms of prior IND submissions eg our CMO has been involved in upwards of twenty plus IND submissions, there is also a wealth of experience from other senior staff members. He then commented that if even only ONE of those staff members had that much experience particularly from an Aussie company that was submitting an FDA IND, that was terrific.
Paradigmers, this adds to our positive prognosis.
QUESTION 7 - At what point does the FDA become privy to the data accumulated in the various trials? Eg we kick off with a dosing study…after that no doubt the FDA will analyse and assist to determine the best dose (lowest amount of drug for efficacy), then the real trial (called 002) starts. (Slated to go from Q3 2021 through to Q1 2023), then 003 kicks off Q4 2022 and is slated to finish Q3 2023.
Usually it won't be until the very end of Phase 3 that we would get any data back. This is subject to Fast Track however Mr X stated clearly that it would be up to the sponsor to assess whether the data coming back warrants a discussion as to what are the prospects of having a case of sufficiently good evidence.
Mr X does remember at least one example in his experience where 75% of the way through a trial the evidence was so compelling that it was deemed to be unethical to keep the placebo group going, It would've been at that stage that the sponsor would have successfully negotiated with the FDA to expedite the process.
Waiting for the eventual day...that stamp of approval.
TIPS?
We didn't even think to ask him for advice/tips, he was forthcoming unprompted. A valuable resource indeed.
1) As a 'Tip' Mr X suggested that if there is a well known individual that is a continual thorn in the side and always takes the negative, plays down positives and seems to have arguments more against the drug and its performance specially if this person is resident in the US, then a good idea is to actually get them on board on the review panel. It insures that later the FDA cant second/draft this same person to vote against you when it's time to discuss the data and determine if the drug has merits to go ahead to registration.
2) Do not come up/introduce any surprises especially in terms with the Review/Advisory Committee which occurs later on. At a high level this involves a broad invitation, eg any of the treating physicians could be called upon.It is really good advice to get some good medical advisors to do the groundwork and be present if need be during the process. (Mozz view - we have this covered with good staff already based in the US).
QUESTION 8 - How many Aussie companies have successfully submitted an IND in the USA in the last 5 or so years?
This was a last minute question, I had some basic idea of the number that I had once asked a an Aussie BioPharma Analyst but I wasn't sure if I got the number right and it's always good to verify this info, I love my secondary sources of info!
I was expecting an answer from Mr X of about 20 to 30...the answer?
Around 10 was the answer.
Just 10 or so have had successful IND submissions in roughly the last 5 years.
Mozz view - Yep, Hall of fame stuff if we make it to P3...we will know soon enough!
An Aussie Hall of fame exclusive club - When will we make it? I want to see us up on that wall of fame.
THE AUSSIE SCENE
Mr X went on to state that the number of successful trials from Aussie companies were very low. Many of them simply do not have the sources of funds and calibre of staff to see through the huge amounts of works required. A lot of them have done the SAD and MAD studies 2 but do not have the intention and/or fortitude to carry on for the longer term to see out a trial, they groom themselves to sell the asset.
Mr X was somewhat surprised that we hadn't partnered up yet and was impressed that we are going through it alone, [Mozz note: I think this adds to the quality of underlying asset we are dealing with. We know what we have and what its capable of, why would we sell out so early, would anyone just sell the Golden Goose when its laying consistent eggs of a great carat value and has many years of future production?].
CONCLUSION
Fascinating interview and I dare say we will line up another one at some intermediary future point to discuss how we are tracking and any accumulated questions any of us have into the exciting P3 and beyond process. I for one would love to query him on his thoughts about the next phase ie. Registration and I am already starting to think of question around the Marketing and Labelling side.
Many thanks indeed again to Axel and of course Mr X.
Axel and I will organise a nice bottle of Red as a small thank you on behalf of us all at PAR HC to be presented to Mr X.
DYOR is always recommended.
FOOTNOTES
1) For more info on clinical trial blinding see this site:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1118396/
2) SAD = Single Ascending Dosing
MAD = Multi Ascending Dosing
See this link for further info:
https://www.nuventra.com/services/pharmacokinetics-pharmacodynamics/multiple-ascending-dose-studies/
(20min delay)